PSYC62: Drugs and the Brain
Lecture 8: Opiates (Narcotics)
No group of drugs that better captures the "double-edged sword" paradox than the opiates, which
includes opium (form which everything else is derived?), morphine, heroine, synthetic compounds.
Used for centuries for pain, continue to play an important role in modern pharmacology.
We now recognize what we didn't realize before, the other edge of the sword, the ability to produce
very high dependence?
The Opiates (Narcotics): Source
Opiate drugs are derived from the extracts of the opium poppy seed
o Non synthetic opiates are derived from opium which is itself derived from the poppy plant.
o When the petals fall off the plant after it has bloomed, what's left is an egg-seized pod. When
the pod is scored with a knife, it excretes a milky substance, which is dried to produce opium (a
Main active ingredient in opium is morphine
o Morphine is the main psychoactive alkaloid derived from opium.
There are a variety of natural and synthetic opiates (e.g., morphine, codeine, heroin,
o Codeine, like morphine, is responsible for the psychoactive effects.
o Heroine is "semi-synthetic", produced by modifying the morphine molecule?
o Many other synthetic opiates to bind specifically to opiate receptors (eg. methadone which is
used in opiate addiction, and oxycodone/oxycontin, also found to have a high abuse liability)
Figure 1: Schedule Control
Opiates are schedule II, high abuse, high liability, but do have some medical uses (of chronic pain)
Exception: Heroin is an opiate but it's a schedule I drug (no approved medical use)
Different level of codeine can lead to different classification (schedule 3: codeine in Tylenol) Figure 2
Morphine is considered the prototype opiate analgesic, so it's given a potency rating of 1 in the above
table and all the other drugs are compared to morphine in terms of potency.
Fentanyl is 100 times more potent than morphine, 50 times more than heroin, but it has been
approved as an anaesthetic in surgical procedures, compared to heroin which is a schedule I drug.
The risk of using opiates in pain relief is that addiction may develop, but relatively few patients who
use these drugs under direct medical supervision actually develop addiction.
When pain is severe and chronic enough, tolerance will inevitably develop and higher doses and more
potent drugs will be required, and in some cases only morphine will be useful in diminishing pain in
There are some instance (in the UK?) where heroin is actually prescribed for pain relief in terminal
patients, although prescription of heroin for pain relief in North America has never been approved in
any conditions, but the question comes up of whether it should be, like in the UK
Should heroin be prescribed to the terminally ill?
1. Heroin is more addicting than morphine
More difficult to manage it safely
2. Consider the case of Oxycontin
Oxycontin is a drug that was relatively recently designed and marketed for treating
chronic and severe pain, but it has been found that it has a high abuse liability, and there
is a wave of abuse and addiction now associated with Oxycontin use
Oxycontin is 1.5 times more potent than morphine, but heroin is 2 times more potent,
slippery slope associated with approving heroin for pain relief
If Oxycontin is associated with this wave of abuse, what would happen if heroin was
available in a similar fashion
1. Is addiction relevant in a terminally ill patient?
If the person doesn't have very long to live and their pain can only be managed with
heroin addiction maybe shouldn't be a foremost concern
2. Patients receiving high and frequent doses of morphine are probably already dependent
by the time heroin treatment would be begun
Prescribing heroin would ever be a first line of action by a physician, and if it's the only
way to manage the pain, should we be all that concerned about the potential of
dependence? 3. Heroin is converted to morphine in the brain and thus morphine is the active chemical in
producing pain relief in both cases
Once heroin (semi-synthetic opiate) crosses the BBB, it is rapidly converted into
morphine and the morphine molecule is what affects the receptors
Heroin is distributed much more rapidly to the brain, which is why it has a higher abuse
4. Heroin could reduce pain at lower doses and with fewer drug administrations
One might accomplish the same degree of pain relief with larger and more frequent
doses of morphine, but terminal patients often lose weight and become thin and won't
be able to tolerate such high dose and frequent addiction
Percent of high school seniors
reporting elicit or non-medical
uses of these drugs, steady
increase in the last 10 or 15 so
Since 2000, a fairly high
percentage of this kind of drug
use can be attributed to
Opiates influences the activity of monoamine systems (inhibits norepinephrine and activates
o Whereas the psychostimulants active all the monoamines (MAs), opiates have differential
effects on these systems depending on which MA you're talking about.
o Opiates directly inhibit the NE system directly by???, but they activate DA and serotonin
indirectly through dis-inhibition?
Opiates act to mimic activity in the brain’s endorphin systems by stimulating opiate receptors
o Naturally occurring morphine-like substances in the brain (endorphins), involved in pain
mediation and producing pleasure.
o In the early 1970s, researchers at Johns Hopkins discovered brain receptors that responded
selectively to opiates (bind opiates).
o Why do we naturally have these? The presence of these receptors must mean that there is
some natural brain chemical that binds to these receptors
o The search was on to discover the brain's own opiates. In 1975 the class of chemicals called the
endorphins were discovered
o The opiates in part produce their activity by triggering the receptors of the endorphins?
The direct effects of opiates are primarily inhibitory
o They are primarily depressants of the CNS, but they can have increasing effects (like on the DA
system) through disinhibition. Figure 4
We sometimes collectively call them all "endorphins",
but there are three subfamilies
Endorphins is a contraction for "endgoenous morphine"
Endogenous opioid peptides include:
1. Endorphins (e.g., β-endorphin)
Released and produce pain relief
2. Enkephalins (e.g., met-enkephalin, leu-
3. Dynorphins (e.g., dynorphin A, dynorphin B)
Endorphins are part of a natural pain relief system, after certain kinds of pain or stress endorphins are
released and they produce analgesia due to their activity at the endorphin receptors. This may show
why on a battlefield for example, a person may have crazy injuries but for a time they won't feel pain
because the endorphins kick in an reduce pain naturally
Endorphins are also associated with the "runner's high" because after a period of physical activity they
are released and they act in natural reward system in the brain to produce pleasure
This dopamine reward system mediates the rewarding effects of drugs like opiates
So the endorphins are associated with pain mediation and also indirectly with pleasure.
Opioid receptors are located in a variety of brain regions; for e.g.,
o Analgesia pathways (e.g., thalamus, spinal cord, periaqueductal gray)
Found in spinal cord and brainstem regions that are associated with
transmitting pain information
o VTA and nucleus accumbens
o Locus coeruleus
A brainstem region that contains mostly NE cells, involved in
regulating the stress response and managing anxiety and stress
Activation of opiate receptors in these areas inhibit NE and regulate stress
The potency with which the endogenous and exogenous opiates have for the three opioid receptor
Endogenous and non-endogenous opiates bind to opiate receptors
Opiate receptor subtypes:
o mu (µ)
o delta (δ)
o kappa (κ) Endogenous agonists
o Enkephalins and endorphins
act mostly on delta, dynorphin
mess with the kappa.
o Almost exclusively acting on
the mu opioid receptors, so in
the area of opiate addiction,
the mu receptors are the main
focus of research.
Recent evidence that dynorphin
acting on kappa may also have a role
in addiction and dependence.
o Buprenorphine promising new
treatment for addiction
o These mixed a-a and
antagonists are commonly
used to treat opiate addiction.
o Especially potent at the mu
Opiates found in abundance in the reward system, they act to increase DA
3 neighboring neurons, converging on one synapse
Terminal of a DA neuron releasing dopamine, that started off in the VTA
GABA containing terminal ending.
Morphine acts to increase the
availability of DA, like psychostimulants,
but through a different mechanism
Morphine binds to the terminal endings
of the GABA-releasing cell
The GABA will, in normal conditions,
send a signal to the DA cell to not
release DA. When the GABA neuron is
inhibited, the DA cell is dis-inhibited
and you get an increased availability of
DA Historical Perspective
Smoking or consuming opium orally is an ancient practice
o Has been used for thousands of years (smoking was used by Sumerians, medical use by
Egyptians and Romans
o Recognized throughout the world for its pharmacological effects
By the beginning of the nineteenth century, opium dependence was widespread in Asia
o Not a problem in Europe or North America
In 1803, the process of allowing separation of morphine from opium was developed in Germany
o This did lead to use and dependence in Europe and in North America
o Although opium is dependence-forming, morphine is the purified form of the most active
ingredient in opium, and is therefore 10 times more potent? Same as how cocaine is more
potent than just chewing in a coca leaf.
o Concurrent with the separation of morphine from opium was the development of the
hypodermic syringe, so injecting morphine was a common practice and contributed to the
o Injecting morphine is even more potent than taking it orally.
Because of the rapid and potent pain-relieving properties of injectable morphine, it became the
treatment of choice during recovery from injury in wartimes.
o Readily prescribed with soldiers for injuries
o Morphine addiction became a big problem and dealing with the withdrawal effects were even
harder to manage than the pain itself that the morphine was used for.
o Morphine taken orally was higher, but injection is more potent
In 1914, under the Harrison Act, control of opiate drugs was placed in the hands of physicians
o At this time opiates became regulated drugs
o Physicians determined if an individual had a valid medical need for opiates (which included
heroin at this time)
o By 1924, heroin was no longer prescribed and became a schedule I drug. in 1914 when opiates
became a classified drug, heroin was initially a schedule II drug? But then it went to schedule I.
After a period of decline in the 1980’s, increased availability and abuse of heroin has occurred
o The number of addiction cases involving heroin and the number of emergency room visits
involving heroin has doubled since? Number of heroin addicts is???
o NIDA - national institute of drug abuse, estimates that opiates (mostly heroin) are directly
responsible for more than a thousand deaths per year
Opiates: Medicinal Uses
Analgesia/ pain relief
o Pain relief is the primary medical benefit of narcotics.
o Act to block the sensation of pain from being transmitted to pain from spinal cord to brain
o Reduces the negative effects connected to pain
o The pain sensations are not completely blocked, but the responses to pain are changed,
presumably through the effects on the reward system
o The individual isn't completely numb to pain but they can better manage the pain in a more
positive way via the actions of opiates in the reward pathway
o Important to understand the relationship between opiates and the rewarding system, not only
to understand addiction, but also to understand how pain is managed. Cough suppression
o Opiates slow the activity of the cough control centre of the brain which is located in the
o Codeine has long been used as a cough suppressant, high level of efficacy in suppressing
o Used to be available in over the counter cough syrups but now only available through
o Many synthetic variants that are similar to opiates are found in cough medication in place of
codeine, they have selective cough suppressant effects but don't have the same addiction
potential as codeine
o Opiates are used to treat opiate addiction
o Methadone is the primary maintenance therapy that's being used
o Pharmacological antagonists and mixed a-a's like buprenorphine are being used effectively to
Modes of Intake
o Can be taken orally, most opiates are readily absorbed through the GI tract, although a given
dose of the drug has a more potent effect if injected
Injected (Intravenous, intramuscular, subcutaneous)
o Heroin addicts tend to inject up to 4 times a day, on an ongoing basis.
o As opposed to cocaine and amphetamine which are taken in a binge patterns where they do
nothing but administer for a while, and then crash and not take for a few days, then resume
o With opiates it's different, steady administration
o Can be injected in many ways, but intravenous is the most effective
o Effects of IV injection is felt within seconds, whereas intramuscular or subcutaneous needs like
5-8 minutes to feel the effects. IV injection has higher abuse potential
o Taken intranasally
o Most opiates including heroin are absor